tbuckley/cabot-search huggingface dataset:
Optimization of Albuminuria-Lowering Treatment in Diabetes by Crossover Rotation to Four Different Drug Classes: A Randomized Crossover Trial
Authors: Viktor Rotbain Curovic, Niels Jongs, Marjolein Y.A.M. Kroonen, Emilie H. Zobel, Tine W. Hansen, Taha Sen, Gozewijn D. Laverman, Adriaan Kooy, Frederik Persson, Peter Rossing, Hiddo J.L. Heerspink
Journal: Diabetes Care (2023)

OBJECTIVE Renin–angiotensin system (RAS) inhibitors decrease the urinary albumin to creatinine ratio (UACR) but are ineffective in up to 40% of patients. We hypothesized that rotation through different drug classes overcomes RAS inhibitor resistance and tested this in a randomized crossover trial. RESEARCH DESIGN AND METHODS We assigned 26 adults with type 1 diabetes and 37 with type 2 diabetes and UACR between 30 and 500 mg/g and estimated glomerular filtration rate &amp;gt;45 mL/min/1.73 m2 to 4-week treatment periods with telmisartan 80 mg, empagliflozin 10 mg, linagliptin 5 mg, and baricitinib 2 mg in random order, separated by 4-week washout periods. Each participant was then re-exposed for 4 weeks to the drug that induced that individual’s largest UACR reduction. Primary outcome was the difference in UACR response to the best-performing drug during the confirmation period versus UACR response to the other three drugs. RESULTS There was substantial variation in the best-performing drug. Telmisartan was best performing for 33 participants (52%), empagliflozin and linagliptin in 11 (17%), and baricitinib in 8 participants (13%). The individuals’ best-performing drug changed UACR from baseline during the first and confirmatory exposures by a mean of −39.6% (95% CI −44.8, −33.8; P &amp;lt; 0.001) and −22.4% (95% CI −29.7, −12.5; P &amp;lt; 0.001), respectively. The Pearson correlation for first versus confirmatory exposure was 0.39 (P = 0.017). The mean change in UACR with the other three drugs was +1.6% (95% CI −4.3%, 8.0%; P = 0.593 versus baseline; difference versus individuals’ best-performing drug at confirmation, 30.9% [95% CI 18.0, 45.3]; P &amp;lt; 0.001). CONCLUSIONS We demonstrated a large and reproducible variation in participants’ responses to different UACR-lowering drug classes. These data support systematic rotation through different drug classes to overcome therapy resistance to RAS inhibition.
The Nephrologist's Role in Supporting People with CKD and Unplanned Pregnancy Post-Dobbs
Authors: Andrea G. Kattah, Catherine R. Butler
Journal: Journal of the American Society of Nephrology (2023)

1Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota 2Division of Nephrology, Department of Medicine, Kidney Research Institute, University of Washington, Seattle, Washington 3Veterans Affairs Health Services Research and Development Center of Innovation for Veteran-Centered and Value-Driven Care, Seattle, Washington Correspondence: Dr. Andrea Kattah, Division of Nephrology and Hypertension, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. Email: [email protected] A.G.K. and C.R.B. contributed equally to this work. Published online ahead of print. Publication date available at www.jasn.org.
In This Issue
Authors: Ruth Williams
Journal: Circulation Research (2023)

Transition in Heart Failure (p 154) Hydrogen sulfide reduces fibrosis in the failing heart, report Li et al.Hydrogen sulfide (H 2 S) is a signaling molecule with a variety of functions, many of which are protective of cardiovascular health.It promotes vasodilation, preserves endothelial function and delays atherogenesis, for example, and has antiinflammatory and anti-oxidant properties.With these benefits in mind, Li and colleagues investigated whether H 2 S could play a protective and possibly therapeutic role, with regards to heart failure-a condition in dire need of new treatment strategies.The team studied mice with an endothelial-specific genetic deletion of the H 2 S-producing enzyme CSE as well as mice overexpressing the enzyme.When heart failure was experimentally induced in the animals, those lacking CSE had lower exercise capacity, impaired heart function and more cardiac fibrosis than controls, while those overexpressing the protein showed improvements in these measures.Mechanistically, the absence of CSE prompted the endothelial cells to adopt a mesenchymal phenotype (EndoMT), which increased the abundance of profibrotic cells.Providing H 2 S to CSE-lacking cells prevented signs of EndoMT, while providing it to CSElacking mice with heart failure reduced hypertrophy and improved heart function and exercise performance, all of which suggests H 2 S could indeed have therapeutic potential.
Antiviral effects and tissue exposure of tetrandrine against SARS‐CoV‐2 infection and COVID‐19
Authors: Jia Liu, Furun Wang, Xi Wang, Shiyong Fan, Yufeng Li, Mingyue Xu, Hengrui Hu, Ke Liu, Bohong Zheng, Lingchao Wang, Huanyu Zhang, Jiang Li, Wei Li, Wenpeng Zhang, Zhihong Hu, Ruiyuan Cao, Xiaomei Zhuang, Manli Wang, Wu Zhong
Journal: MedComm (2023)

Tetrandrine (TET) has been used to treat silicosis in China for decades. The aim of this study was to facilitate rational repurposing of TET against SARS-CoV-2 infection. In this study, we confirmed that TET exhibited antiviral potency against SARS-CoV-2 in the African green monkey kidney (Vero E6), human hepatocarcinoma (Huh7), and human lung adenocarcinoma epithelial (Calu-3) cell lines. TET functioned during the early-entry stage of SARS-CoV-2 and impeded intracellular trafficking of the virus from early endosomes to endolysosomes. An in vivo study that used adenovirus (AdV) 5-human angiotensin-converting enzyme 2 (hACE2)-transduced mice showed that although TET did not reduce pulmonary viral load, it significantly alleviated pathological damage in SARS-CoV-2-infected murine lungs. The systemic preclinical pharmacokinetics were investigated based on in vivo and in vitro models, and the route-dependent biodistribution of TET was explored. TET had a large volume of distribution, which contributed to its high tissue accumulation. Inhaled administration helped TET target the lung and reduced its exposure to other tissues, which mitigated its off-target toxicity. Based on the available human pharmacokinetic data, it appeared feasible to achieve an unbound TET 90% maximal effective concentration (EC
Multi-omics microsampling for the profiling of lifestyle-associated changes in health
Authors: Xiaotao Shen, Ryan Kellogg, Daniel J Panyard, Nasim Bararpour, Kevin Erazo Castillo, Brittany Lee-McMullen, Alireza Delfarah, Jessalyn Ubellacker, Sara Ahadi, Yael Rosenberg-Hasson, Ariel Ganz, Kévin Contrepois, Basil Michael, Ian Simms, Chuchu Wang, Daniel Hornburg, Michael P Snyder
Journal: Nature Biomedical Engineering (2023)

Abstract Current healthcare practices are reactive and use limited physiological and clinical information, often collected months or years apart. Moreover, the discovery and profiling of blood biomarkers in clinical and research settings are constrained by geographical barriers, the cost and inconvenience of in-clinic venepuncture, low sampling frequency and the low depth of molecular measurements. Here we describe a strategy for the frequent capture and analysis of thousands of metabolites, lipids, cytokines and proteins in 10 μl of blood alongside physiological information from wearable sensors. We show the advantages of such frequent and dense multi-omics microsampling in two applications: the assessment of the reactions to a complex mixture of dietary interventions, to discover individualized inflammatory and metabolic responses; and deep individualized profiling, to reveal large-scale molecular fluctuations as well as thousands of molecular relationships associated with intra-day physiological variations (in heart rate, for example) and with the levels of clinical biomarkers (specifically, glucose and cortisol) and of physical activity. Combining wearables and multi-omics microsampling for frequent and scalable omics may facilitate dynamic health profiling and biomarker discovery.
Federated learning for predicting histological response to neoadjuvant chemotherapy in triple-negative breast cancer
Authors: Jean Ogier du Terrail, Armand Leopold, Clément Joly, Constance Béguier, Mathieu Andreux, Charles Maussion, Benoît Schmauch, Eric W. Tramel, Etienne Bendjebbar, Mikhail Zaslavskiy, Gilles Wainrib, Maud Milder, Julie Gervasoni, Julien Guerin, Thierry Durand, Alain Livartowski, Kelvin Moutet, Clément Gautier, Inal Djafar, Anne-Laure Moisson, Camille Marini, Mathieu Galtier, Félix Balazard, Rémy Dubois, Jeverson Moreira, Antoine Simon, Damien Drubay, Magali Lacroix-Triki, Camille Franchet, Guillaume Bataillon, Pierre-Etienne Heudel
Journal: Nature Medicine (2023)
The NHS staffing crisis cannot be resolved without reform of the doctors’ pay review body
Authors: Vishal Sharma
Journal: BMJ (2023)

The NHS staffing crisis cannot be resolved without reform of the doctors' pay review body Vishal Sharma BMA consultants committee chair An independent, fair process for setting the pay of healthcare workers is an alluring idea.No wonder, then, that we have heard numerous claims from government ministers in recent weeks that their hands are tied by the pay review process when it comes to deciding doctors' pay.Yet such claims that this process remains "independent" have been undermined year on year by government interference and attempts to fix what the review bodies can recommend.
Clinicopathological and predictive value of MAIT cells in non-small cell lung cancer for immunotherapy
Authors: Lin Shi, Jinying Lu, Da Zhong, Meijuan Song, Jian Liu, Wenhua You, Wen-Hui Li, Lin Lin, Dongyan Shi, Yun Chen
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Immune-checkpoint inhibitors (ICIs) remain ineffective in a large group of non-small cell lung cancer (NSCLC) patients. Mucosal-associated invariant T (MAIT) cells, a population of unconventional innate-like T lymphocytes abundant in the human body, play important roles in human malignancies. Little is known about the immune characteristics of MAIT cells in NSCLC and correlation with prognosis and response rate of ICIs treatment. Methods To investigate the distribution, activation status, and function of MAIT cells in NSCLC patients and their correlations with anti-PD-1 immunotherapy, MAIT cells in peripheral blood, tumor and paratumor samples from NSCLC patients with or without anti-PD-1 immunotherapy were analyzed using flow cytometry and single-cell RNA-sequencing. Results MAIT cells were enriched in the tumor lesions of NSCLC patients migrating from peripheral blood via the CCR6-CCL20 axis. Both peripheral and tumor-infiltrating MAIT cells displayed an exhausted phenotype with upregulated PD-1, TIM-3, and IL-17A while less IFN-γ. Anti-PD-1 therapy reversed the function of circulating MAIT cells with higher expression of IFN-γ and granzyme B. Subcluster MAIT-17s (defined as cells highly expressing exhausted and Th17-related genes) mainly infiltrated in the non-responsive tissues, while the subcluster MAIT-IFNGRs (cells expressing genes related to cytotoxic function) were mainly enriched in responsive tissues. Moreover, we found predictive value of circulating MAIT cells for anti-PD-1 immunotherapy in NSCLC patients. Conclusions MAIT cells shifted to an exhausted tumor-promoting phenotype in NSCLC patients and the circulating MAIT subset could be a predictor for patients who respond to anti-PD-1 immunotherapy.
Wearable full-body motion tracking of activities of daily living predicts disease trajectory in Duchenne muscular dystrophy
Authors: Valeria Ricotti, Balasundaram Kadirvelu, Victoria Selby, Richard Festenstein, Eugenio Mercuri, Thomas Voit, A. Aldo Faisal
Journal: Nature Medicine (2023)

Artificial intelligence has the potential to revolutionize healthcare, yet clinical trials in neurological diseases continue to rely on subjective, semiquantitative and motivation-dependent endpoints for drug development. To overcome this limitation, we collected a digital readout of whole-body movement behavior of patients with Duchenne muscular dystrophy (DMD) (n = 21) and age-matched controls (n = 17). Movement behavior was assessed while the participant engaged in everyday activities using a 17-sensor bodysuit during three clinical visits over the course of 12 months. We first defined new movement behavioral fingerprints capable of distinguishing DMD from controls. Then, we used machine learning algorithms that combined the behavioral fingerprints to make cross-sectional and longitudinal disease course predictions, which outperformed predictions derived from currently used clinical assessments. Finally, using Bayesian optimization, we constructed a behavioral biomarker, termed the KineDMD ethomic biomarker, which is derived from daily-life behavioral data and whose value progresses with age in an S-shaped sigmoid curve form. The biomarker developed in this study, derived from digital readouts of daily-life movement behavior, can predict disease progression in patients with muscular dystrophy and can potentially track the response to therapy.
The impact of the COVID-19 pandemic on cardiovascular disease prevention and management
Authors: Caroline E Dale, Rohan Takhar, Raymond Carragher, Michail Katsoulis, Fatemeh Torabi, Stephen Duffield, Seamus Kent, Tanja Mueller, Amanj Kurdi, Thu Nguyen Le Anh, Stuart McTaggart, Hoda Abbasizanjani, Sam Hollings, Andrew Scourfield, Ronan A Lyons, Rowena Griffiths, Jane Lyons, Gareth Davies, Daniel Harris, Alex Handy, Mehrdad A Mizani, Christopher Tomlinson, Johan H Thygesen, Mark Ashworth, Spiros Denaxas, Amitava Banerjee, Jonathan A C Sterne, Paul Brown, Ian Bullard, Rouven Priedon, Mamas A Mamas, Ann Slee, Paula Lorgelly, Munir Pirmohamed, Kamlesh Khunti, Andrew D Morris, Cathie Sudlow, Ashley Akbari, Marion Bennie, Naveed Sattar, Reecha Sofat
Journal: Nature Medicine (2023)
Humoral regulation of iron metabolism by extracellular vesicles drives antibacterial response
Authors: Huijuan Kuang, Geng Dou, Linfeng Cheng, Xiangdong Wang, Haokun Xu, Xuemei Liu, Feng Ding, Xiaoshan Yang, Siying Liu, Lili Bao, Huan Liu, Yao Liu, Bei Li, Yan Jin, Shiyu Liu
Journal: Nature Metabolism (2023)
Soluble and cell-based markers of immune checkpoint inhibitor-associated nephritis
Authors: Meghan E Sise, Qiyu Wang, Harish Seethapathy, Daiana Moreno, Destiny Harden, R Neal Smith, Ivy A Rosales, Robert B Colvin, Sarah Chute, Lynn D Cornell, Sandra M Herrmann, Riley Fadden, Ryan J Sullivan, Nancy J Yang, Sara Barmettler, Sophia Wells, Shruti Gupta, Alexandra-Chloe Villani, Kerry L Reynolds, Jocelyn Farmer
Journal: Journal for ImmunoTherapy of Cancer (2023)

Non-invasive biomarkers of immune checkpoint inhibitor-associated acute tubulointerstitial nephritis (ICI-nephritis) are urgently needed. Because ICIs block immune checkpoint pathways that include cytotoxic T lymphocyte antigen 4 (CTLA4), we hypothesized that biomarkers of immune dysregulationpreviously defined in patients with congenital CTLA4 deficiency, including elevated soluble interleukin-2 receptor alpha (sIL-2R) and flow cytometric cell-based markers of B and T cell dysregulation in peripheral blood may aid the diagnosis of ICI-nephritis.
Comments on roles of circulating tumor cells in the metastatic cascade and tumor immune escape: biology and clinical translation
Authors: Maria Jose Serrano, Umberto Malapelle
Journal: Journal for ImmunoTherapy of Cancer (2023)

Liquid biopsy (LB) is, without a doubt, one of the fundamental pillars of precision medicine. In this context, Circulating Tumor Cells (CTCs) are one of the more important LB components and one of the more unknown and 'misunderstood'. In this review, Alix-Panabieres and Pantel described and
Liquid biopsies coming of age: biology, emerging technologies, and clinical translation- An introduction to the JITC expert opinion special review series on liquid biopsies
Authors: Mark D. Stewart, Valsamo Anagnostou
Journal: Journal for ImmunoTherapy of Cancer (2023)

Liquid biopsies are gaining momentum as minimally invasive means for cancer detection, characterization, monitoring, and interception. Composed of five expert-opinion review articles and five accompanying expert-physician viewpoints, this Journal for ImmunoTherapy of Cancer Special Review Series focuses on capturing and synthesizing the current state of science of liquid biopsies and their clinical relevance for cancer immunotherapy and beyond.
Cytosolic aldose metabolism contributes to progression from cirrhosis to hepatocarcinogenesis
Authors: Z Oaks, A Patel, N Huang, G Choudhary, T Winans, T Faludi, D Krakko, M Duarte, J Lewis, M Beckford, S Blair, R Kelly, S K Landas, F A Middleton, J M Asara, S K Chung, D R Fernandez, K Banki, A Perl
Journal: Nature Metabolism (2023)
A wearable motion capture suit and machine learning predict disease progression in Friedreich’s ataxia
Authors: Balasundaram Kadirvelu, Constantinos Gavriel, Sathiji Nageshwaran, Jackson Ping Kei Chan, Suran Nethisinghe, Stavros Athanasopoulos, Valeria Ricotti, Thomas Voit, Paola Giunti, Richard Festenstein, A. Aldo Faisal
Journal: Nature Medicine (2023)

Abstract Friedreichʼs ataxia (FA) is caused by a variant of the Frataxin ( FXN ) gene, leading to its downregulation and progressively impaired cardiac and neurological function. Current gold-standard clinical scales use simplistic behavioral assessments, which require 18- to 24-month-long trials to determine if therapies are beneficial. Here we captured full-body movement kinematics from patients with wearable sensors, enabling us to define digital behavioral features based on the data from nine FA patients (six females and three males) and nine age- and sex-matched controls, who performed the 8-m walk (8-MW) test and 9-hole peg test (9 HPT). We used machine learning to combine these features to longitudinally predict the clinical scores of the FA patients, and compared these with two standard clinical assessments, Spinocerebellar Ataxia Functional Index (SCAFI) and Scale for the Assessment and Rating of Ataxia (SARA). The digital behavioral features enabled longitudinal predictions of personal SARA and SCAFI scores 9 months into the future and were 1.7 and 4 times more precise than longitudinal predictions using only SARA and SCAFI scores, respectively. Unlike the two clinical scales, the digital behavioral features accurately predicted FXN gene expression levels for each FA patient in a cross-sectional manner. Our work demonstrates how data-derived wearable biomarkers can track personal disease trajectories and indicates the potential of such biomarkers for substantially reducing the duration or size of clinical trials testing disease-modifying therapies and for enabling behavioral transcriptomics.
Next-generation ctDNA-driven clinical trials in precision immuno-oncology
Authors: Charu Aggarwal, Natasha B Leighl
Journal: Journal for ImmunoTherapy of Cancer (2023)

Based on an improvement in our understanding of the biology and underpinnings of the biology of cancer, we have witnessed a sea change in our ability to deliver novel therapies, such as immunotherapy and targeted therapy for the appropriate subset of patients. The study of tumor clonal evolution has
Opportunities and challenges in the diagnostic utility of dermal interstitial fluid
Authors: Mark Friedel, Ian A P Thompson, Gerald Kasting, Ronen Polsky, David Cunningham, Hyongsok Tom Soh, Jason Heikenfeld
Journal: Nature Biomedical Engineering (2023)

The volume of interstitial fluid (ISF) in the human body is three times that of blood. Yet, collecting diagnostically useful ISF is more challenging than collecting blood because the extraction of dermal ISF disrupts the delicate balance of pressure between ISF, blood and lymph, and because the triggered local inflammation further skews the concentrations of many analytes in the extracted fluid. In this Perspective, we overview the most meaningful differences in the make-up of ISF and blood, and discuss why ISF cannot be viewed generally as a diagnostically useful proxy for blood. We also argue that continuous sensing of small-molecule analytes in dermal ISF via rapid assays compatible with nanolitre sample volumes or via miniaturized sensors inserted into the dermis can offer clinically advantageous utility, particularly for the monitoring of therapeutic drugs and of the status of the immune system. This Perspective argues that dermal interstitial fluid cannot be generally considered a diagnostically useful proxy for blood, yet that it can offer advantageous utility for the monitoring of therapeutic drugs and of the status of the immune system.
Tissue adaptation and clonal segregation of human memory T cells in barrier sites
Authors: Maya M L Poon, Daniel P Caron, Zicheng Wang, Steven B Wells, David Chen, Wenzhao Meng, Peter A Szabo, Nora Lam, Masaru Kubota, Rei Matsumoto, Adeeb Rahman, Eline T Luning Prak, Yufeng Shen, Peter A Sims, Donna L Farber
Journal: Nature Immunology (2023)
Complex I inhibitor of oxidative phosphorylation in advanced solid tumors and acute myeloid leukemia: phase I trials
Authors: Timothy A. Yap, Naval Daver, Mikhila Mahendra, Jixiang Zhang, Carlos Kamiya-Matsuoka, Funda Meric-Bernstam, Hagop M. Kantarjian, Farhad Ravandi, Meghan E. Collins, Maria Emilia Di Francesco, Ecaterina E. Dumbrava, Siqing Fu, Sisi Gao, Jason P. Gay, Sonal Gera, Jing Han, David S. Hong, Elias J. Jabbour, Zhenlin Ju, Daniel D. Karp, Alessia Lodi, Jennifer R. Molina, Natalia Baran, Aung Naing, Maro Ohanian, Shubham Pant, Naveen Pemmaraju, Prithviraj Bose, Sarina A. Piha-Paul, Jordi Rodon, Carolina Salguero, Koji Sasaki, Anand K. Singh, Vivek Subbiah, Apostolia M. Tsimberidou, Quanyun A. Xu, Musa Yilmaz, Qi Zhang, Yuan Li, Christopher A. Bristow, Meenakshi B. Bhattacharjee, Stefano Tiziani, Timothy P. Heffernan, Christopher P. Vellano, Philip Jones, Cobi J. Heijnen, Annemieke Kavelaars, Joseph R. Marszalek, Marina Konopleva
Journal: Nature Medicine (2023)
YTHDF2 orchestrates tumor-associated macrophage reprogramming and controls antitumor immunity through CD8+ T cells
Authors: Shoubao Ma, Baofa Sun, Songqi Duan, Jingjing Han, Tasha Barr, Jianying Zhang, Marc B Bissonnette, Marcin Kortylewski, Chuan He, Jianjun Chen, Michael A Caligiuri, Jianhua Yu
Journal: Nature Immunology (2023)
An epithelial cell-derived metabolite tunes immunoglobulin A secretion by gut-resident plasma cells
Authors: Simona Ceglia, Alyssa Berthelette, Kelsey Howley, Yun Li, Benedikt Mortzfeld, Shakti K. Bhattarai, Nicole K. H. Yiew, Ying Xu, Robert Brink, Jason G. Cyster, Lora V. Hooper, Gwendalyn J. Randolph, Vanni Bucci, Andrea Reboldi
Journal: Nature Immunology (2023)
A high-quality Ixodes scapularis genome advances tick science
Authors: Sandip De, Sarah B. Kingan, Chrysoula Kitsou, Daniel M. Portik, Shelby D. Foor, Julia C. Frederick, Vipin S. Rana, Nicole S. Paulat, David A. Ray, Yan Wang, Travis C. Glenn, Utpal Pal
Journal: Nature Genetics (2023)
Notch1 mutations drive clonal expansion in normal esophageal epithelium but impair tumor growth
Authors: Emilie Abby, Stefan C. Dentro, Michael W. J. Hall, Joanna C. Fowler, Swee Hoe Ong, Roshan Sood, Albert Herms, Gabriel Piedrafita, Irina Abnizova, Christian W. Siebel, Moritz Gerstung, Benjamin A. Hall, Philip H. Jones
Journal: Nature Genetics (2023)

Abstract NOTCH1 mutant clones occupy the majority of normal human esophagus by middle age but are comparatively rare in esophageal cancers, suggesting NOTCH1 mutations drive clonal expansion but impede carcinogenesis. Here we test this hypothesis. Sequencing NOTCH1 mutant clones in aging human esophagus reveals frequent biallelic mutations that block NOTCH1 signaling. In mouse esophagus, heterozygous Notch1 mutation confers a competitive advantage over wild-type cells, an effect enhanced by loss of the second allele. Widespread Notch1 loss alters transcription but has minimal effects on the epithelial structure and cell dynamics. In a carcinogenesis model, Notch1 mutations were less prevalent in tumors than normal epithelium. Deletion of Notch1 reduced tumor growth, an effect recapitulated by anti-NOTCH1 antibody treatment. Notch1 null tumors showed reduced proliferation. We conclude that Notch1 mutations in normal epithelium are beneficial as wild-type Notch1 favors tumor expansion. NOTCH1 blockade may have therapeutic potential in preventing esophageal squamous cancer.